Opposing actions of adenosine A2a and dopamine D2 receptor activation on GABA release in the basal ganglia: evidence for an A2a/D2 receptor interaction in globus pallidus.

There is increasing evidence that adenosine (ADO) and dopamine (DA) interact directly in the basal ganglia via actions at ADO A2a and DA D2 receptors, respectively. The purpose of this study was to determine 1) the extent to which these receptors modulate endogenous GABA release in discrete regions of the rat basal ganglia and 2) whether GABA release is modulated by a direct and opposing interaction between ADO A2a and DA D2 receptors. Tissue slices of striatum (STR) containing globus pallidus (GP; STR/GP) and micropunches of STR, GP, and substantia nigra pars reticulata (SNr) were studied. Radioligand binding demonstrated that ADO A1, ADO A2a, and DA D2 receptors were present in each of the tissue preparations with the exception of SNr, in which ADO A2a receptors were not detected. Stimulation of ADO A2a receptors with CGS 21680 (1-10 nM) increased electrically stimulated GABA release in STR/GP slices and GP micropunches. Consistent with the lack of A2a receptors in SNr, CGS 21680 had no effect on GABA release from this region. In contrast, stimulation of DA D2 receptors with N-0437 (1-100 nM) inhibited evoked GABA release from STR/GP slices and both GP and SNr micropunches. The D2-mediated inhibition of GABA release in GP was abolished in the presence of CGS 21680 (10 nM). These experiments demonstrate that stimulation of ADO A2a and DA D2 receptors has opposing effects on endogenous GABA release in STR and GP. These opposing actions may explain the antagonistic interactions between ADO and DA that have been observed in behavioral studies and support the hypothesis that the striatopallidal efferent system is an important anatomical substrate for the A2a/D2 receptor interaction.

Repeated intravenous cocaine administration to rats produces behavioral sensitization without changing brain cocaine levels.

Repeated intraperitoneal (i.p.) administration of cocaine to rats results in behavioral sensitization. However, augmented brain cocaine levels are also produced by this treatment. In the present study, a 43% increase in cocaine levels was observed in striatum in response to eight once-daily i.p. injections of cocaine (10 mg/kg). It has been suggested that this dispositional change does not occur with intravenous (i.v.) cocaine administration. In agreement with this suggestion, the striatal cocaine levels observed following either a single i.v. injection or eight once-daily i.v. injections of cocaine (1 mg/kg) were similar. Nonetheless, the rats became behaviorally sensitized in response to the repeated i.v. cocaine administration. These results suggest that the increased brain levels of cocaine observed following repeated i.p. cocaine administration cannot completely account for behavioral sensitization.